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Role of neutrophils and eosinophils in bacterial ligand-induced vasculitis

中性粒细胞和嗜酸性粒细胞在细菌配体诱导的血管炎中的作用

基本信息

批准号：
10710315
负责人：
Moshe Arditi
金额：
$ 19.17万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10710315
关键词：
Abdominal Aortic Aneurysm Acute Affect Alternative Therapies Aneurysm Animal Model Aortitis Arteritis Blood Vessels Cardiovascular system Cell Wall Cells Child Childhood Chronic Clinical Trials Coronary Coronary artery Cytokine Signaling Data Development Disease Disease model Etiology Family Fever Gene Expression Genetic Heart Diseases Histologic Human IL1R1 gene Immune Immunoglobulin G Immunologics In Vitro Incidence Infiltration Inflammasome Inflammation Inflammation Mediators Inflammatory Innate Immune Response Interleukin-1 Interleukin-1 beta Intervention Intravenous Immunoglobulins Lactobacillus casei Lesion Ligands Maps Modeling Monoclonal Antibodies Mucocutaneous Lymph Node Syndrome Mus Myocarditis Neutrophil Infiltration Pathogenesis Pathogenicity Pathologic Pathology Patients Prevention Prevention approach Production Proteins Research Priority Resistance Risk Role Serine Protease Severities Signal Transduction Testing Tissue Sample Tissues Transcript Vasculitis abdominal aorta anakinra animal data antagonist coronary arteritis cytokine eosinophil experimental study extracellular in vivo infection risk member mouse model neutrophil new therapeutic target novel strategies novel therapeutics prevent receptor vascular inflammation vascular injury

项目摘要

PROJECT ABSTRACT Kawasaki disease (KD), the leading cause of acquired heart disease among children in the US, is an acute febrile illness and systemic vasculitis of unknown etiology that causes coronary artery aneurysms (CAA) and can result in long-term cardiovascular sequelae. While Intravenous immunoglobulin (IVIG) treatment lowers CAA development to 5%, up to 20% of KD patients are IVIG-resistant and have a greater risk for coronary inflammation. A better understanding of the immune pathological mechanisms leading to the development of KD vasculitis is one of the highest research priorities. Recent genetic data, and data from experimental mouse model of KD, have all converged on the critical role of IL-1 signaling in pathogenesis of the KD lesions. Two clinical trials using the IL-1R antagonist were recently initiated in KD patients who do not respond to IVIG. Studies identifying the underlying immune-specific mechanisms involved in IL-1β production are needed and little is known regarding which immune cell subsets produce IL-1β during KD vasculitis. By using a murine model of KD vasculitis associated with coronary artery inflammation and abdominal aorta aneurysm development, we found that inflamed vascular lesions are infiltrated by neutrophils and eosinophils that express high levels of Il1b, Nlrp3 and Padi4 transcripts, the latter one encodes PAD4, a protein known for its crucial role in neutrophils extracellular traps (NETs) formation. Our preliminary data also demonstrate that PAD4 inhibition blocks not only IL-1β production in vitro but also prevents LCWE-induced KD vasculitis in vivo, how this blockade directly affect NETs and eosinophils extracellular traps (EETs) formation and their IL-1β production remain unknown. Our new data also demonstrate that IL-33 is pathogenic and may promote the pro-inflammatory functions of eosinophils through the IL-33 receptor, ST2. Therefore, based on our preliminary data, the central hypothesis from this application is that activated neutrophils and eosinophils promote LCWE-induced KD vasculitis through a PAD4-dependent release of NETs and EETs, bioactive IL-1β and other pro-inflammatory mediators. Here, we will investigate the role of eosinophils and neutrophils during murine KD vasculitis and propose interventions aiming to block IL-1β production by those cells and PAD4 signaling, as well as the disruption of IL-33 signaling on eosinophils, which may result in decreased inflammation and the prevention of KD lesions. To investigate this central hypothesis, we propose the following specific aims: 1) Determine the role of infiltrating neutrophils during LCWE-induced KD vasculitis, 2) Determine the role of tissue-infiltrating eosinophils during LCWE-induced KD vasculitis and 3)Determine the role of PAD4 in neutrophils and eosinophils during LCWE-induced KD vasculitis. The successful conclusion of these studies will significantly alter the way KD is understood and influence the development of new therapies.

项目摘要